Stem cells and early-stage placental development

By Matt Shipman

There’s a lot we still don’t know about the early stages of placental development in humans — in part because there are practical, ethical and legal constraints that make it difficult to obtain relevant placental samples. But researchers may be closing in on a solution.

One way to address this dilemma is to use human embryonic stem cells to develop trophoblasts, the precursors to placental cells. But there’s been
intense debate about whether trophoblasts obtained from hESCs have the same features as “true” trophoblasts.

A recent paper in the
Journal of Biological Chemistry opens a new chapter in the debate, lending credence to the notion that bona fide trophoblasts can be obtained from hESCs.

One of the key arguments against hESC-derived trophoblasts has been that the promoter region of the ELF5-2b gene in these cells is methylated, whereas it is not methylated in trophoblasts in vivo. A second argument has been that hESC-derived trophoblasts show expression of HLA class I antigens — unlike trophoblasts in vivo.

Those arguments have now been disproven.

“We’ve shown that you can form trophoblasts from hESCs that are both demethylated in the ELF5-2b promoter region and that show downregulated expression of HLA class I antigens,” said
Balaji Rao, a biological engineering researcher at North Carolina State University and corresponding author of the JBC paper.

“Our work supports the claim that hESCs can be used to create models for understanding trophoblast differentiation and early placental development,” Rao added.

In addition, the Rao paper identifies conditions that allow researchers to target the derivation of the two major types of trophoblasts: syncytiotrophoblasts and extravillous trophoblasts. Syncytiotrophoblasts are multinucleate, hormone-producing cells. Extravillous trophoblasts are a class of cells that perform various functions, including anchoring the placenta to the uterine wall and remodeling the mother’s arteries to establish blood flow to the placenta.

The researchers found that if signaling by Activin/Nodal proteins is blocked, hESC-derived progenitor trophoblasts differentiate into extravillous trophoblasts. But if Activin/Nodal signaling is present, the progenitor cells differentiate into syncytiotrophoblasts.

“There is still an enormous amount of work to be done in this field – this is only the beginning,” Rao said. “But hopefully our recent work will move the research community one step closer to developing a model system that can capture and explain the dynamic nature of trophoblasts in vivo over the course of gestation. It is a huge challenge.”

Rao’s research was funded by the National Science Foundation. The lead author of the JBC paper is his former Ph.D. student,
Prasenjit Sarkar, who is now a biochemistry postdoctoral fellow in Boston University’s School of Medicine.

Matt Shipman is a public information officer at North Carolina State University and a freelance science writer. He also writes the Communication Breakdown blog for Nature's SciLogs blog network.